ABSTRACT This competitive renewal application continues to address the molecular genetic basis of kidney development and renal epithelial cell regeneration. During previous funding periods, we have made significant breakthroughs in defining the mechanisms of Pax2 protein function in development and disease. The current application will extend and expand our studies in several new directions. First, we will identify and characterize Pax2 target genes in vivo using novel EGFP alleles for identifying mutant cell types. Second, we will determine whether targets activated by Pax2 are direct and require the PTIP/Mll histone methyltransferase complex. The expression of developmental targets will be assessed in animal models of renal disease and in regenerating kidneys. In the second aim, we will screen for inhibitors and activators of Pax2 activity using cell based assays and chemical libraries. We have developed assays for high throughput screening that can detect both activators and inhibitors of Pax2 function. Given all that we know about DNA binding and protein- protein interactions, we will be able to test the mechanisms of inhibition or activation directly. Such small molecules may be very useful for attenuating renal polycystic disease or renal cell cancers, in which Pax2 over expression is a determining factor. The genetic and cell biological mechanisms of renal epithelial cell regeneration are poorly characterized. Our work will define the transcriptional paths required for kidney development and regeneration and can provide new avenues for therapeutic intervention in renal disease.